Aerosol preparation comprising sealed container and enclosed therein aerosol composition containing marcolide compound

ABSTRACT

An aerosol preparation comprising an enclosure enclosing an aerosol composition containing a macrolide compound (e.g., tacrolimus) serving as an active ingredient has a problem such that the formulation of the aerosol composition is changed with the passage of time so as to reduce the ratio of the active ingredient in the aerosol composition because the macrolide compound as the active ingredient is partly adsorbed to a “gasket” of a valve part made of resinous material. In an aerosol preparation of the invention comprising an aerosol composition containing a macrolide compound and an enclosure enclosing the aerosol composition, a valve part of the enclosure has a “gasket” made of at least one resinous material selected from butyl rubber, ethylene-propylene rubber, chloroprene rubber, polyethylene, polybutylene terephthalate, polyacetal, polyamide, polytetrafluoroethylene, polypropylene and thermoplastic elastomer, thereby solving the problem.

TECHNICAL FIELD

The invention relates to an aerosol preparation comprising an enclosureenclosing an aerosol composition containing a macrolide compound.

BACKGROUND ART

There are well-known conventional macrolide compounds such as rapamycin,tacrolimus and askomycin, which are generated by Streptomyces, analoguesthereof, and derivatives thereof. The term “macrolide compound” is thegeneric name of compounds with 12 members or more, which belongs tomacrolide lactones. Preferable examples of the macrolide compound aretricyclic compounds and pharmaceutically acceptable salts thereof.

Such tricyclic compounds, and rapamycin and its derivatives, have asimilar basic structure, i.e., tricyclic macrolide structure, and atleast one of the similar biological properties (for example,immunosuppressive activity).

On the other hand, a medical aerosol preparation (herein, combination ofan aerosol composition and an enclosure enclosing the aerosolcomposition is referred to as an “aerosol preparation”) is broadly usedin the field of medicine as a drug delivery system, i.e., an inhaler,adapted to deliver a medicinally active substance in a finely dividedform along with inspired air into the recipient's airway for thetreatment of attacks of bronchial asthma, for instance.

An example of conventional aerosol composition used for the medicalaerosol preparation contains the macrolide compound as an activeingredient, and an example of the macrolide compound is tacrolimus. Thisconventional aerosol composition may further contain lubricantconsisting of medium-chain fatty acid triglyceride (a saturated fattyacid triglyceride [CH3(CH2)nCOOH; n=4 to 10]), propellant consisting ofliquefied hydrofluoroalkane, e.g., HFA-134a, and/or so on as occasiondemands. Such an aerosol composition is disclosed in InternationalPublication WO 97/10806, for example.

As disclosed in International Publication WO 99/43575, for instance, ametered dose inhaler (MDI) serves as an example of the enclosure forenclosing such an aerosol composition. The metered dose inhaler mainlycomprises a vessel part, a cap part, and a valve part. The valve part isused for spraying out a dose of the aerosol composition from the vesselpart, and the valve part has a structural portion functioning as agasket (packing) in contact with the cap part, and/or interposed betweenthe vessel part and the cap part, so as to prevent the aerosolcomposition from leaking out. Hereinafter and in attending claims, sucha structural portion of the valve part having the above function isreferred to as a “gasket”.

SUMMARY OF THE INVENTION

Resin is broadly used as material for constituting the “gasket” of thevalve part of the metered dose inhaler. However, it has been found thatthe macrolide compound including the tacrolimus, when prepared forinhalation and enclosed in the metered dose inhaler, is partly adsorbed(or sorbed) to the resinous material made into the “gasket” of the valvepart. This phenomenon suggests that the formulation of the aerosolcomposition enclosed and preserved in the metered dose inhaler ischanged with the passage of time so that the ratio of active ingredientin the aerosol composition is reduced. Particularly, the reduction ofthe content of active ingredient by the adsorption thereof to the“gasket” of the valve part is serious in the case that the density ofactive ingredient in the aerosol composition when initially enclosed inthe enclosure is low.

Considering the above situation, the present invention is intended toprovide an aerosol preparation in which an aerosol compositioncontaining a macrolide compound such as tacrolimus can be reserved for along time without change of the formulation thereof with the passage oftime.

The problem to be solved by the invention has been described as theabove. Solution of the problems will now be described.

To solve the above-mentioned problem, what material is selected formaking the “gasket” of the valve part of the enclosure is important. Thematerial must adsorb no (strictly, very little) macrolide compound suchas tacrolimus.

The material also requires such a certain “strength” and a certain“softness” as to function as the “gasket” of the valve part. The balancebetween strength and softness must be adjusted considering thestructural location of the “gasket” in the valve part.

From this viewpoint, optimal materials for making a “gasket” of anaerosol preparation comprising an enclosure enclosing an aerosolcomposition containing a macrolide compound (such as tacrolimus) servingas an active ingredient have been sought. As a result, a solvableaerosol preparation is as follows:

An aerosol preparation comprises an aerosol composition containing amacrolide compound, and an enclosure enclosing the aerosol composition.The enclosure includes a valve part having a “gasket” made of at leastone material selected from butyl rubber, ethylene-propylene rubber,chloroprene rubber, polyethylene, polybutylene terephthalate,polyacetal, polyamide, polytetrafluoroethylene, polypropylene andthermoplastic elastomer.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a sectional side view of a metered dose inhaler when it is notapplied.

FIG. 2 is a sectional side view of the metered dose inhaler when it isapplied.

FIG. 3 is a diagram showing a relation of adsorptivity of an activeingredient in an aerosol composition to each of resinous materials.

FIG. 4 is a diagram showing variation of a ratio of rest of an activeingredient in an aerosol composition with the passage of time when theaerosol preparation is kept in stationary.

BEST MODE FOR CARRYING OUT THE INVENTION

An aerosol preparation of the invention will be detailed.

The following examples are listed up as preferable resinous materialsfor making the “gasket”. Incidentally, the “resinous materials” in thisapplication are defined as macromolecular materials such as rubbers,plastics and thermoplastic elastomers. Each of the following exampleresinous materials may have additives broadly used for prevention ofdegradation or improvement of properties, such as aprocessing-stabilization agent (example: Irgafos 168, Irgafos P-EPQ (thetrademarks of Chiba Specialty Chemicals Hldg)), an ultraviolet absorberagent (example: Chimassorb 81, Tinuvin 213 (the trade marks of ChibaSpecialty Chemicals Hldg), Sumisorb 400 (the trade mark of SumitomoChemical Co., Ltd.)) and an anti-oxidant (example: Sumilizer GA80 (thetrade mark of Sumitomo Chemical Co., Ltd.), Irganox 245, Irganox B215(the trade marks of Chiba Specialty Chemicals Hldg)), without departurefrom the scope of the invention.

Butyl Rubber: a butyl rubber containing 0.5 to 2.5 mole % degree ofunsaturation (containing a 0.5 to 2.5 mole % isoprene), e.g., Code No.540 of Valois, etc.

Ethylene-Propylene Rubber: an ethylene-propylene rubber containing a 15to 50 mole % propylene, or an ethylene-propylene diene rubber(ethylene-propylene rubber polymerized with a little third componentsuch as ENB, 1,4-hexadiene, dicyclopentadiene), e.g., Code No. 808 ofValois, etc.

Chloroprene Rubber: a sulfur-modified, non-sulfur-modified or highlychrystalline chloroprene rubber, e.g., Neoprene (the trademark of DuPont), Code No. 210B of Valois, etc.

Polyethylene: a low-density, medium-density or high-densitypolyethylene, e.g., Hostalen (the trademark of Bassel Polyolefine), etc.

Polybutylene Terephthalate: a polybutylene terephthalate as acondensation polymer of thetramethylene-glycol(1,4-butanediol) combinedwith terephthalic acid or dimethyl terephthalate, e.g., Valox (thetrademark of General Electric Plastics), etc.

Polyacetal: a homopolymeric polyacetal (polyoxymethylene) or acopolymeric polyacetal, e.g., Delrin (the trademark of Du Pont), Kematal(the trademark of Ticona), etc.

Polyamide: nylon 6, nylon 12, nylon 11, nylon 610, nylon 612 or nylon66, e.g., Zytel (the trademark of Du Pont), etc.

Polytetrafluoroethylene: Code No. 8070 of Nikko Shokai, etc.

Polypropylene: PP1013H1 of ExxonMobil, etc.

Thermoplastic Elastomer: at least one rubber as a soft segment selectedfrom a rubber group consisting of butyl rubber, ethylene propylenerubber and chloroprene rubber, mixed with at least one plastic as a hardsegment selected from a plastic group of polyethylene, polybutyleneterephthalate, polyacetal, polyamide, polytetrafluoroethylene andpolypropylene, e.g., Code No. S8501 of Valois, etc.

Of the above resinous materials for making the “gasket”, furtherpreferable resinous materials are as follows:

1) butyl rubbers

2) ethylene-propylene rubbers

3) chloroprene rubbers

4) a polyolefin thermoplastic elastomer, which is at least one rubber asa soft segment selected from a rubber group of butyl rubber,ethylene-propylene rubber and chloroprene rubber, mixed with at leastone plastic as a hard segment selected from a plastic group ofpolyethylene, polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene (further preferably, apolyolefin thermoplastic elastomer as a mixture of butyl rubber andpolyethylene (the mixture (weight) ratio is between about 2:3 to about3:2))

In addition to the above thermoplastic elastomer, a polystyrenethermoplastic elastomer (e.g., a mixture of polystyrene andpolybutadiene, or a mixture of polystyrene and polyisoprene), a1,2-polybutadiene thermoplastic elastomer (e.g., a mixture ofsyndiotactic 1,2-polybutadien and amorphous 1,2-polybutadien), apolyolefin thermoplastic elastomer (e.g., a mixture of polyethylene orpolypropylene and ethylene-butene rubber), a polyurethane thermoplasticelastomer (a mixture of polyurethane and polyester, or a mixture ofpolyurethane and polyether), a polyester thermoplastic elastomer (e.g.,a mixture of polyester and polyether), a polyamide thermoplasticelastomer (e.g., a mixture of polyamide and polyester, or a mixture ofpolyamide and polyether), a chlorinated polyethylene thermoplasticelastomer (e.g., a mixture of block type chlorinated polyethylene andrandom chlorinated polyethylene), a polyvinyl chloride thermoplasticelastomer (e.g., a mixture of polyvinyl chloride and amorphous polyvinylchloride, or a mixture of polyvinyl chloride and acrylonitrile-butadienerubber), or a polyfluorocarbon thermoplastic elastomer (e.g., a mixtureof fluorocarbon resin and fluororubber) may serve as the resinousmaterial for making the “gasket”, if it adsorbs no (strictly, verylittle) macrolide compound.

As mentioned above, the resinous material for making the “gasket” mustbe selected so as to ensure an adequate balance between the certainstrength and the certain softness. From this viewpoint, the resinousmaterial must be selected considering the structural location of the“gasket” in the valve part.

Generally, the “gasket” constituting the valve part comprises thefollowing three portions (not limited to this structure):

1) a gasket portion for ensuring airtightness of an inside (enclosed bya vessel part and a cap part) of the enclosure, namely, a neck gasketportion;

2) a gasket portion contacting a slide member so as to airtightlyisolate the inside of the enclosure from a metering chamber, namely, afirst gasket portion; and

3) a gasket portion contacting the slide member so as to airtightlyisolate the metering chamber from the outside of the enclosure, namely,a second gasket portion.

The metering chamber is a structural portion of the valve part intowhich a fixed volume of the aerosol composition is taken out from theinside of the enclosure. The slide member is a structural portion of thevalve part, which slides toward the inside of the enclosure so as tobring the metering chamber into communication with the inside of theenclosure, and which slides outward from the enclosure so as to bringthe metering chamber into communication with an outside of the enclosureand to spray out the fixed volume of the aerosol composition.

In the present application, the above three gasket portions are referredto as the neck gasket portion, the first gasket portion and the secondgasket portion, respectively.

The neck gasket portion for ensuring the airtightness of an enclosingchamber serving as the inside of the enclosure requires some degree ofsoftness (plasticity or elasticity), and requires adhesion to tightlycontact the vessel part, the cap part, or another portion of the valvepart.

Also, the neck gasket portion having a large area in touch with theaerosol composition in the enclosing chamber is especially required toadsorb very little amount of the macrolide compound.

The first and second gasket portions airtightly and reciprocally slidesagainst the slide member hundreds of times (depending on the filledvolume) before the aerosol composition filled in the enclosure iscompletely used.

Therefore, the softness of the first and second gasket portions isrequired to be higher than that of the neck gasket portion.

Of course, the amount of the aerosol composition adsorbed to the firstand second gasket portions is requested to be as little as possible.However, the first and second gasket portions, which are smaller thanthe neck gasket portion, have small surface areas in touch with theaerosol composition filled in the enclosure. It is guessed that themacrolide compound is adsorbed to every surface of the valve part intouch with the aerosol composition. Therefore, the material for makingthe first and second gasket portions is not required to adsorb so littleamount of the macrolide compound as the material for making the neckgasket portion.

Thus, the material for making the first and second gasket portions canbe selected attaching importance to the high softness.

In consideration of the above, preferable resinous material for makingeach of the gasket portions of the valve part are listed up as follows:

For the Neck Gasket Portion: a butyl rubber, e.g., Code No. 540 ofValois; or a thermoplastic elastomer, preferably, a mixture of butylrubber and polyethylene (further preferably, the mixture (weight) ratiois set between about 2:3 to about 3:2), e.g., Code No. S8501 of Valois

For the First and Second Gasket Portions: a butyl rubber, e.g., Code No.540 of Valois; an ethylene-propylene rubber, e.g., Code No. 808 ofValois; or a chloroprene rubber, e.g., Neoprene (the trade mark of DuPont) or Code No. 210B of Valois (especially preferably, the chloroprenerubber, e.g., Code No. 210B of Valois)

Especially preferably, considering that the adsorption of the macrolidecompound such as the tacrolimus to the resinous material should berestricted within a desirable range, the resinous material selected formaking the “gasket” has such a characteristic that, just after theresinous material having 39 mm² surface area has been soaked in the 10ml aerosol composition having the 0.025 wt % macrolide compound for amonth under a condition of 75% relative humidity and 40° C., the amountof the remaining macrolide compound in the aerosol composition is notless than 80% of the amount of the initial macrolide compound before thesoaking.

The term “macrolide compound” is the generic name of compounds with 12members or more, which belongs to macrolide lactones. Especiallypreferable examples of the macrolide compound are tacrolimus, a hydratethereof and salts thereof.

An example of the “aerosol composition containing a macrolide compound”contains an active ingredient consisting of the macrolide compound(preferably, tacrolimus), and a propellant consisting of a liquefiedhydrofluoroalkane. The aerosol composition may further contain amedium-chain fatty acid triglyceride serving as a lubricant. Examples ofthe medium-chain fatty acid triglyceride are such commercial products asMiglyol (the trademark of Sasol) 812, Panacete (the trademark of NOFcorporation) 810, Coconard (the trademark of Kao corporation), Miritol(the trademark of Hankel-Hakusui) GM, ODO (the trademark of the NisshinOil Mills, Ltd.), etc.

Examples of the “liquefied hydrofluoroalkane” are HFA-134a, HFA-227,etc. One of them may be selected, or more than one may be selected to bemixed together. If the aerosol composition is prepared with theliquefied hydrofluoroalkane, the content of the tacrolimus solvable inthe liquefied hydrofluoroalkane is not more than about 0.15 wt %.

The “aerosol composition containing a macrolide compound” can beprepared by the method normally used in the corresponding technologicalfield.

A common valve used in the corresponding technological field can be usedas the “valve part”. Preferably, a valve part of a metered dose inhalerserves as the valve part.

Preferably, the “valve part” includes a metering chamber member, ahousing and a protection ring to be discussed later in addition to theabove-mentioned “gasket” and slide member.

In the “aerosol preparation comprising an enclosure enclosing an aerosolcomposition containing a macrolide compound” according to the presentinvention, structural parts other than the above-mentioned parts can beprepared in an ordinary way used by a skilled person in thecorresponding technological field.

Preferable embodiments of the present invention will be described asfollows (the present invention is not limited to the followingembodiments):

Preferably, the macrolide compound of the present invention istacrolimus or hydrated tacrolimus.

Further preferably, the content of the tacrolimus or hydrated tacrolimusin the aerosol composition is not more than 0.15 wt %.

Preferably, the aerosol composition of the present invention contains aliquefied hydrofluoroalkane.

Further preferably, the liquefied hydrofluoroalkane is one of HFA-134aand HFA-227, or a mixture of the two.

Preferably, the aerosol composition of the present invention contains amedium-chain fatty acid triglyceride.

Preferably, the enclosure of the present invention is a metered doseinhaler.

Preferably, material made into the “gasket” of the present invention ismade of at least one resinous material selected from butyl rubber,ethylene-propylene rubber, chloroprene rubber and thermoplasticelastomer.

Preferably, the selected at least one resinous material made into the“gasket” of the present invention is the thermoplastic elastomer, whichis at least one rubber selected from a rubber group consisting of butylrubber, ethylene-propylene rubber and chloroprene rubber, mixed with atleast one plastic selected from a plastic group of polyethylene,polybutylene terephthalate, polyacetal, polyamide, polytetrafluoroethylene and polypropylene.

Further preferably, the thermoplastic elastomer is a mixture of butylrubber and polyethylene.

Preferably, the selected at least one resinous material made into the“gasket” of the present invention has such a characteristic that, justafter the resinous material having 39 mm² surface area has been soakedin the 10 ml aerosol composition having the 0.025 wt % macrolidecompound for a month under a condition of 75% relative humidity and 40°C., the amount of the remaining macrolide compound in the aerosolcomposition is not less than 80% of the amount of the initial macrolidecompound before the soaking.

Preferably, the “gasket” of the present invention comprises the neckgasket portion for ensuring airtightness of the enclosure, wherein theneck gasket portion is made of at least one resinous material selectedfrom butyl rubber, ethylene-propylene rubber, chloroprene rubber,polyethylene, polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene, polypropylene and thermoplastic elastomer.

Further preferably, the selected at least one resinous material madeinto the neck gasket portion is the butyl rubber or the thermoplasticelastomer.

Preferably, the material made into the neck gasket portion of thepresent invention is a thermoplastic elastomer which is at least onerubber selected from a rubber group consisting of butyl rubber,ethylene-propylene rubber and chloroprene rubber, mixed with at leastone plastic selected from a plastic group consisting of polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene.

Further preferably, the thermoplastic elastomer made into the neckgasket portion is a mixture of butyl rubber and polyethylene.

Preferably, the selected at least one resinous material made into theneck gasket portion of the present invention has such a characteristicthat, just after the resinous material having 39 mm² surface area hasbeen soaked in the 10 ml aerosol composition having the 0.025 wt %macrolide compound for a month under a condition of 75% relativehumidity and 40° C., the amount of the remaining macrolide compound inthe aerosol composition is not less than 80% of the amount of theinitial macrolide compound before the soaking.

Preferably, the valve part of the present invention is provided with ametering chamber, into which a fixed volume of the aerosol compositionis taken out from the inside of the enclosure, and a slide member. Theslide member slides toward the inside of the enclosure so as to bringthe metering chamber into communication with the inside of theenclosure. The slide member slides outward from the enclosure so as tobring the metering chamber into communication with an outside of theenclosure and to spray out the fixed amount of the aerosol composition.The “gasket” of the valve part includes the neck gasket portion forensuring airtightness of the enclosure, the first gasket portioncontacting the slide member so as to airtightly isolate the inside ofthe enclosure from the metering chamber, and the second gasket portioncontacting the slide member so as to airtightly isolate the meteringchamber from the outside of the enclosure. Each of the neck gasketportion, the first gasket portion and the second gasket portion is madeof at least one resinous material selected from butyl rubber,ethylene-propylene rubber, chloroprene rubber, polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene, polypropylene and thermoplastic elastomer.

Preferably, according to the present invention, the neck gasket portionis made of thermoplastic elastomer which is at least one rubber selectedfrom a rubber group consisting of butyl rubber, ethylene-propylenerubber and chloroprene rubber, mixed with at least one plastic selectedfrom a plastic group consisting of polyethylene, polybutyleneterephthalate, polyacetal, polyamide, polytetrafluoroethylene andpolypropylene, and each of the first and second gasket portions is madeof butyl rubber, ethylene-propylene rubber or chloroprene rubber.

Further preferably, according to the present invention, the neck gasketportion is made of thermoplastic elastomer which is a mixture of butylrubber and polyethylene, and the first and second gasket portions aremade of chloroprene rubber.

Preferably, according to the present invention, the selected at leastone resinous material made into each of the neck gasket portion, thefirst gasket portion and the second gasket portion has such acharacteristic that, just after the resinous material having 39 mm²surface area has been soaked in the 10 ml aerosol composition having the0.025 wt % macrolide compound for a month under a condition of 75%relative humidity and 40° C., the amount of the remaining macrolidecompound in the aerosol composition is not less than 80% of the amountof the initial macrolide compound before the soaking.

Preferably, the valve part of the present invention is provided with ametering chamber member, a housing and a slide member. If at least oneof the metering chamber member, the housing and the slide member is madeof resinous material, the resinous material is at least one selectedfrom a plastic group consisting of polyethylene, polybutyleneterephthalate, polyacetal, polyamide, polytetrafluoroethylene andpolypropylene.

Further preferably, the selected resinous material is polybutyleneterephthalate.

Further preferably, the selected at least one resinous material has sucha characteristic that, just after the resinous material having 39 mm²surface area has been soaked in the 10 ml aerosol composition having the0.025 wt % macrolide compound for a month under a condition of 75%relative humidity and 40° C., the amount of the remaining macrolidecompound in the aerosol composition is not less than 80% of the amountof the initial macrolide compound before the soaking.

Preferably, the valve part of the present invention is provided with aprotection ring made of at least one resinous material selected from aplastic group consisting of polyethylene, polybutylene terephthalate,polyacetal, polyamide, polytetrafluoroethylene and polypropylene.

Further preferably, the selected resinous material made into theprotection ring is polyethylene or polyamide.

Further preferably, the selected at least one resinous material madeinto the protection ring has such a characteristic that, just after theresinous material having 39 mm² surface area has been soaked in the 10ml aerosol composition having the 0.025 wt % macrolide compound for amonth under a condition of 75% relative humidity and 40° C., the amountof the remaining macrolide compound in the aerosol composition is notless than 80% of the amount of the initial macrolide compound before thesoaking.

The aerosol preparation comprising an aerosol composition containing amacrolide compound and an enclosure enclosing the aerosol compositionaccording to the present invention has a prolonged pharmaceuticalquality assurance such as to preserve the formulation of the aerosolcomposition therein from change with time.

The following embodiment of the aerosol preparation and various empirictest results will be detailed so as to confirm that the above effect isassured by optimal selection of material for making the “gasket” of thevalve part of the enclosure.

Embodiment of Aerosol Preparation Comprising Enclosure Enclosing AerosolComposition Containing Macrolide Compound

Referring to FIGS. 1 and 2, description will be given of a metered doseinhaler 1 serving as an example of an enclosure for constituting the“aerosol preparation comprising the enclosure enclosing an aerosolcomposition containing a macrolide compound” of the present invention,that is an enclosure applicable to preparation for inhalation.

Incidentally, the aerosol preparation according to the present inventionis applicable to not only the following preparation for inhalation butalso any other uses such as preparation of application for external use,medicine for nebulizer or medicine for internal use.

The following description will be given on the assumption forconvenience that an arrow A in FIG. 1 points “upward”.

As shown in FIG. 1, metered dose inhaler 1 mainly comprises a vesselpart 2, a cap part 3, and a valve part 4.

Vessel part 2 for enclosing the aerosol composition is a main body ofinhaler 1 formed into a substantially cylindrical shape having an openbottom surface and a closed top surface. Vessel part 2 is made ofaluminum alloy in this present embodiment.

Cap part 3 is provided for hermetically sealing vessel part 1 afterfilled with the aerosol composition. Cap part 3 also serves as afastener for fastening valve part 4 to vessel part 1.

Cap part 3, which is made of aluminum alloy similar to vessel part 2, isformed into a substantially cylindrical shape having an open bottomsurface and a closed top surface. Cap part 3 is formed with a downwardlyexpanded portion 3 a at its central bottom portion. Expanded portion 3 ais crimped sideward so as to retain valve part 4 therein.

Expanded portion 3 a has a center hole from which a slide member 8serving as a component member of valve part 4 projects downward. A spaceenclosed by vessel part 2, cap part 3 and valve part 4, serving as anenclosing chamber 13, is filled with the aerosol composition containingtacrolimus, for example, as an active ingredient.

Valve part 4 serves as a gasket (packing) in contact with cap part 3 orinterposed between vessel part 2 and cap part 3 so as to prevent theaerosol composition from leaking out, and is used for spraying a fixedvolume of the aerosol composition outward from inhaler 1.

Valve part 4 in the present embodiment mainly comprises a housing 5, aprotection ring 6, a neck gasket 7, slide member 8, a spring 9, ametering chamber member 10, a first gasket 11, a second gasket 12 and soon.

With respect to the shape of housing 5, two cylindrical upper and lowerhalf portions having different diameters are layered. The lower halfportion is diametrically larger than the upper half portion. The topsurface of housing 5 is closed, and the bottom surface of housing 5 isopened. An inner portion of the upper half portion of housing 5 servesas a spring chamber 14, in which a spring 9 is disposed.

The upper half portion of housing 5 is provided at its peripheralsurface with slits 5 a,5 a,5 a for communicating spring chamber 14therein to enclosing chamber 13 serving as a space filled with theaerosol composition.

Protection ring 6 is a member for supporting vessel part 2, i.e., forpreventing vessel part 2 from being plastically pressed inwardly whencap part 3 fitted on vessel part 2 is plastically deformed so as tohermetically seal the aerosol composition. Protection ring 6, which issubstantially ring-shaped in this embodiment, and neck gasket 7 areexternally provided on the upper half portion of housing 5.

Neck gasket 7 for ensuring the airtightness of metered dose inhaler 1 isa substantially discoid member having a center hole in the presentembodiment.

When the upper peripheral edge of cap part 3 is deformed centripetallyso as to fit an annular recess 2 a formed on the peripheral side surfaceof vessel part 2, the bottom edge of vessel part 2 is pressed downwardso that the lower surface of neck gasket 7 comes to tightly fit to theinner surface of the bottom wall of cap part 3, and the bottom edgeportion of vessel part 2 comes to abut against the upper surface of neckgasket 7.

In this way, neck gasket 7 is elastically or plastically deformed sothat the edge surface of neck gasket 7 surrounding the center holetightly contacts the outer peripheral surface of the lower half portionof housing 5, thereby ensuring the airtightness of enclosing chamber 13serving as the inside space of metered dose inhaler 1.

Substantially columnar slide member 8 is disposed in housing 5 so as tobe slidable upward and downward (i.e., in a withdrawing direction to theinside of inhaler 1 and in a projecting-out direction to the outside ofinhaler 1).

Slide member 8 is formed at intermediate portions of the side surfacethereof with two radially expanded engaging portions 8 a and 8 b.

In this condition, spring 9 is disposed in a spring chamber 14 servingas the inside space of the upper half portion of housing 5, and engagesto engaging portion 8 a formed on the upper side surface of slide member8 so as to bias slide member 8 downward (i.e., in the projecting-outdirection to the outside of inhaler 1).

In the lower half portion of housing 5, first gasket 11 and secondgasket 12 are disposed up and down with metering chamber member 10therebetween. Slide member 8 vertically penetrates the lower halfportion of housing 5. First gasket 11, second gasket 12, meteringchamber member 10, the lower half portion of housing 5 and the outerperipheral surface of slide member 8 enclose a space serving as ametering chamber 15 into which a fixed volume of the aerosol compositionis taken out from enclosing chamber 13 of metered dose inhaler 1.

First and second gaskets 11 and 12 of this embodiment are substantiallydiscoid members having respective center holes. Slide member 8 slidablyfittingly penetrates the center holes so that first and second gaskets11 and 12 airtightly slidably abut against the outer peripheral surfaceof slide member 8.

Engaging portion 8 b is formed on a side surface of an intermediateportion of slide member 8 in metering chamber 15 below engaging portion8 a.

Slide member 8 downwardly biased by spring 9 is kept in stationary sothat engaging portion 8 b abuts against the upper surface of secondgasket 12 (facing upward to metering chamber 15), when inhaler 1 is notapplied as shown in FIG. 1.

A connection passage 16 and a spraying passage 17 are bored in slidemember 8. The lower portion of slide member 8 projects downward from thehole in expanded portion 3 a of cap part 3 (i.e., to the outside ofinhaler 1).

Connection passage 16 has an upper open end, which is constantly open atthe * outer peripheral surface of slide member 8 so as to face springchamber 14 whether inhaler 1 is applied as shown in FIG. 2 (slide member8 is slid upward) or not applied as shown in FIG. 1 (slide member 8 isdisposed at the lowest slide position so as to make engaging portion 8 babut against the upper surface of second gasket 12).

Connection passage 16 has a lower open end, which is open at the outerperipheral surface of slide member 8 so as to face into spring chamber14 when inhaler 1 is out of use as shown in FIG. 1, and to face intometering chamber 15 when inhaler 1 is applied as shown in FIG. 2.

Spraying passage 17 has an upper open end at the outer peripheralsurface of slide member 8, which is exposed out of inhaler 1 wheninhaler 1 is not applied as shown in FIG. 1, and faces into meteringchamber 15 when inhaler 1 is applied as shown in FIG. 2.

Spraying passage 17 has a lower open end serving as a spraying nozzlehole 17a, which is open downward at the lower end of slide member 8.

The volume of metering chamber 15 is set substantially equal to eachdose of the aerosol composition sprayed from inhaler 1.

Due to the above construction, in the non-applied condition of inhaler 1where slide member 8 is disposed at the lower slide position, as shownin FIG. 1, metering chamber 15 is airtightly isolated from the outsideof inhaler 1, however, metering chamber 15 communicates with enclosingchamber 13 serving as the inner space of inhaler 1 through connectionpassage 16. Namely, while inhaler 1 is not applied, the fixed volume ofaerosol composition corresponding to its one dose is reserved inmetering chamber 15.

In the applied condition of inhaler 1 as shown in FIG. 2 where slidemember 8 is slid upward, metering chamber 15 is airtightly isolated fromenclosing chamber 13, and communicates to the outside of inhaler 1through spraying passage 17.

In this condition, the pressure of the aerosol composition in meteringchamber 15 is substantially equaled to that of the aerosol compositionin enclosing chamber 13 higher than the atmospheric pressure, wherebythe dose of aerosol composition in metering chamber 15 is sprayed fromspraying nozzle hole 17a to the outside of inhaler 1.

Housing 5 and slide member 8 constitute a structural body of valve part4 and are biased by spring 9. Also, metering chamber member 10 isprovided for supporting first and second gaskets 11 and 12 in stationaryagainst sliding of slide member 8. Therefore, metering chamber member10, housing 5 and slide member 8 require high strength.

It is guessed that the macrolide compound including the tacrolimus isadsorbed onto only a surface of a member in touch with the aerosolcomposition. Therefore, housing 5, slide member 8 and protection ring 6having large areas in touch with the aerosol composition in enclosingchamber 13 serving as the inside space of inhaler 1 are especiallyrequested to adsorb very little macrolide compound.

From this viewpoint, it is considered that metal or resin is provided asmaterial for making metering chamber member 10, housing 5, protectionring 6 and slide member 8. If a resinous material is used, it ispreferably selected from a plastic group consisting of polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene. Especially, the polybutyleneterephthalate is preferable.

For example, the selected resinous material may have such acharacteristic that, just after the resinous material having 39 mm²surface area has been soaked in the 10 ml aerosol composition having the0.025 wt % macrolide compound for a month under a condition of 75%relative humidity and 40° C., the amount of the remaining macrolidecompound in the aerosol composition is not less than 80% of the amountof the initial macrolide compound before the soaking.

To constitute valve part 4 in metered dose inhaler 1 of this embodiment,the “gasket”, i.e., neck gasket 7, first gasket 11 and second gasket 12are made of any of butyl rubber, ethylene-propylene rubber, chloroprenerubber, polyethylene, polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene, polypropylene and thermoplastic elastomer.Housing 5, slide member 8, metering chamber member 10 and protectionring 6 are made of any of polybutylene terephthalate, polyacetal,polyamide, polytetrafluoroethylene and polypropylene. Spring 9 is madeof iron material such as stainless steel. Parts of inhaler 1 includingvessel part 2 and cap part 3 excluding valve part 4 are made of metalmaterial such as aluminum alloy.

In addition to the above-mentioned metering chamber member 10, housing5, slide member 8 and protection ring 6, the “gasket” of the valve partcan also be made of selected resinous material having such acharacteristic that, just after the resinous material having 39 mm²surface area has been soaked in the 10 ml aerosol composition having the0.025 wt % macrolide compound for a month under a condition of 75%relative humidity and 40° C., the amount of the remaining macrolidecompound in the aerosol composition is not less than 80% of the amountof the initial macrolide compound before the soaking.

Referring to FIGS. 3 and 4, results of testing absorption of tacrolimusas an example of the macrolide compound serving as an active ingredientin the aerosol composition according to the present invention will bedescribed.

Adsorptivity of Tacrolimus to Resinous Material Constituting Valve Part

FIG. 3 illustrates the adsorptivity of the active ingredient containedin the aerosol composition to each sample resinous material soaked inthe aerosol composition.

The axis of ordinates designates the ratio of (remaining) activeingredient in the aerosol composition to the initial active ingredienttherein when the percentage of the initial active ingredient containedin the aerosol composition is 100%.

The aerosol composition used in the test of FIG. 3 contains a 0.025 wt %macrolide compound. To be concrete, the aerosol composition is asolution that contains 2.5 mg tacrolimus serving as the activeingredient, 10 ml liquefied hydrofluoroalkane (HFA-134a) serving as thepropellant, and a little amount of lubricant normally used for metereddose inhalation.

In the test of FIG. 3, each of the sample resinous materials is formedinto a circular shape having a 5 mm diameter (a 39 mm² surface area),similar to the form of first gasket 11. Each of the sample resinousmaterials is soaked in the aerosol composition solution under thecondition of 75% relative humidity and 50° C. for a month.

The soaked sample materials are BR (butyl rubber), EPDM(ethylene-propylene diene rubber, as a kind of ethylene-propylenerubber), CR (chloroprene rubber), PE (polyethylene, especially,high-density polyethylene), TPE (thermoplastic elastomer, that is amixture of PE and BR in this test), PBT (polybutylene terephthalate),POM (polyoxymethylene as one of polyacetal), PA (polyamide), PTFE(polytetrafluoroethylene), PP (polypropylene), and NBR (nitrile rubber).

Commercial products as the respective sample resinous materials are asfollows:

1) BR: Code No. 540 of Valois

2) EPDM: Code No. 808 of Valois

3) CR: Code No. 210B of Valois

4) High-density PE: the trademark Hostalen GC7260 of Bassel Polyolefine

5) TPE as a mixture of PE and BR: Code No. S8501 of Valois

6) PBT: the trademark Valox 312C-1001 of General Electric Plastics

7) POM: the trademark Kematal M270.14 of Ticona

8) PA (Nylon 66): the trademark Zytel E 101 LNC 10G of Du Pont

9) PTFE: Code No. 8070 of Nikko Shokai

10) PP: PP 1013H1 of ExxonMobil

11) NBR: Code No. 403 of Valois

The ratio of remaining active ingredient is an average of three soakedsamples of each resinous material (n=3).

As understood from FIG. 3, when the nitrile rubber is soaked in theaerosol composition, the active ingredient in the aerosol composition isconsiderably reduced.

In other words, the nitrile rubber soaked in the aerosol compositionadsorbs a considerably large amount of the active ingredient, i.e.,tacrolimus.

The active ingredient in the aerosol composition is scarcely reducedwhen any of the butyl rubber, the ethylene-propylene rubber, thechloroprene rubber, the thermoplastic elastomer as the mixture ofpolyethylene and butyl rubber, the polyethylene, the polybutyleneterephthalate, the polyacetal, the polyamide, thepolytetrafluoroethylene and the polypropylene is soaked in the aerosolcomposition.

In other words, very little tacrolimus serving as the active ingredientis adsorbed to any of the butyl rubber, the ethylene-propylene rubber,the chloroprene rubber, the thermoplastic elastomer as the mixture ofpolyethylene and butyl rubber, the polyethylene, the polybutyleneterephthalate, the polyacetal, the polyamide, thepolytetrafluoroethylene and the polypropylene, which are soaked in theaerosol composition.

Consequently, the butyl rubber, the ethylene-propylene rubber, thechloroprene rubber, the polyethylene, the polybutylene terephthalate,the polyacetal, the polyamide, the polytetrafluoroethylene, thepolypropylene and the thermoplastic elastomer are appropriate formaterial constituting valve part 4 of metered dose inhaler 1. Thethermoplastic elastomer is, preferably, at least one rubber selectedfrom a rubber group consisting of butyl rubber, ethylene-propylenerubber and chloroprene rubber, mixed with at least one plastic selectedfrom a plastic group consisting of polyethylene, polybutyleneterephthalate, polyacetal, polyamide, polytetrafluoroethylene andpolypropylene.

Especially, the butyl rubber, the ethylene-propylene rubber, thechloroprene rubber and the thermoplastic elastomer (preferably, at leastone rubber selected from a rubber group consisting of butyl rubber,ethylene-propylene rubber and chloroprene rubber, mixed with at leastone plastic selected from a plastic group consisting of polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene) are preferable materialshaving the strength and softness required for the gasket.

The polyethylene, polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene are preferable materials formaking the metering chamber member, the housing, the slide member andthe protection ring in the valve part requiring high strength.

Variation of Concentration of Tacrolimus in Aerosol Preparation

FIG. 4 illustrates variation of the ratio of rest of the activeingredient in the aerosol composition with the passage of time when achloroprene rubber or a thermoplastic elastomer serves as a samplematerial for constituting the “gasket” of valve part 4. The axis ofordinates designates the ratio of (remaining) active ingredient in theaerosol composition to the initial active ingredient when the percentageof the initial active ingredient contained in the aerosol composition is100%, and the axis of the axis of abscissas designates the passage oftime.

The aerosol composition used in the test of FIG. 4 contains a 0.025 wt %macrotide compound, similar to that used in the former test ofadsorptivity of tacrolimus to materials for making the valve part, andit is enclosed in the enclosure so as to serve as the aerosolpreparation (the preparation for inhalation shown in FIG. 1).

In the test of FIG. 4, housing 5, slide member 8 and metering chambermember 10 are made of the polybutylene terephthalate (Valox 312C-1001).First and second gaskets 11 and 12 are made of the chloroprene rubber(Code No. 210B of Valois), neck gasket 7 is made of the thermoplasticelastomer as the mixture of polyethylene and butyl rubber (Code No.S8501 of Valois). Protection ring 6 is made of the polyamide (Zytel E101 LNC 10G). They are formed into the respective shapes and assembledtogether as shown in FIG. 1, thereby constituting metering dose inhaler1. The aerosol composition is enclosed in inhaler 1 so as to make anaerosol preparation for inhalation. This aerosol preparation is kept ina condition of 60% relative humidity and 25° C. equivalent to theordinary room condition.

The ratio of remaining active ingredient at each period is an average ofthree soaked samples (n=3).

As understood from FIG. 4, just after twenty four months (two years) haspassed, the remaining amount of active ingredient in the aerosolcomposition, in which the chloroprene rubber or the thermoplasticelastomer sampled as material for making the gasket of the valve part issoaked, is above 90% of the initial amount of active ingredient.

Consequently, when the chloroprene rubber or the thermoplastic elastomeris used as material for making the gasket of the valve part 4, theaerosol composition containing the tacrolimus can be substantiallypreserved for a long time from change of the formulation thereof withtime.

As understood from the result of the test shown in FIG. 3, in thecondition of 40° C. and 75% relative humidity, the chloroprene rubberadsorbs a larger amount of tacrolimus than any other soaked samplematerials, i.e., the butyl rubber, the ethylene-propylene rubber, thepolyethylene, the polybutylene terephthalate, the polyacetal, thepolyamide, the polytetrafluoroethylene, the polypropylene and thethermoplastic elastomer (the mixture of polyethylene and butyl rubber).

Consequently, it is suggested that, when any of the butyl rubber, theethylene-propylene rubber, the polyethylene, the polybutyleneterephthalate, the polyacetal, the polyamide, thepolytetrafluoroethylene, the polypropylene and the thermoplasticelastomer (the mixture of polyethylene and butyl rubber) is selected asthe material for making the “gasket” and soaked in the aerosolcomposition containing tacrolimus under the condition similar to thatfor the test of FIG. 4, the remaining amount of the active ingredient inthe aerosol composition just after the passage of 24 months (two years)is significantly more than 90% of the initial amount of the activeingredient, similarly to the case of the chloroprene rubber soaked inthe aerosol composition.

Consequently, when the “gasket” of valve part 4 is made of any materialselected from the butyl rubber, the ethylene-propylene rubber, thepolyethylene, the polybutylene terephthalate, the polyacetal, thepolyamide, the polytetrafluoroethylene, the polypropylene and thethermoplastic elastomer (preferably, the mixture of polyethylene andbutyl rubber), the aerosol composition containing the tacrolimus can beappropriately preserved for a long time with very little change of thecontent rate in the composition with the passage of time.

INDUSTRIAL APPLICABILITY

The “aerosol preparation comprising an enclosure enclosing an aerosolcomposition containing a macrolide compound” according to the presentinvention is useful in the medical and pharmaceutical industrial field,for example.

1. An aerosol preparation, comprising: an aerosol composition containinga macrolide compound; and an enclosure enclosing the aerosolcomposition, the enclosure including a valve part having a gasketcomprising at least one resinous material selected from the groupconsisting of butyl rubber, ethylene-propylene rubber, chloroprenerubber, polyethylene, polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene, polypropylene and thermoplastic elastomer. 2.The aerosol preparation according to claim 1, wherein the macrolidecompound is tacrolimus or hydrated tacrolimus.
 3. The aerosolpreparation according to claim 2, wherein the content of the tacrolimusor the hydrated tacrolimus in the aerosol composition is not more than0.15 wt %.
 4. The aerosol preparation according to claim 1, wherein theaerosol composition further contains a liquefied hydrofluoroalkane. 5.The aerosol preparation according to claim 4, wherein the liquefiedhydrofluoroalkane is one of HFA-134a and HFA-227, or a mixture of them.6. The aerosol preparation according to claim 1, wherein the aerosolcomposition further contains a medium-chain fatty acid triglyceride. 7.The aerosol preparation according to claim 1, wherein the enclosure is ametered dose inhaler.
 8. The aerosol preparation according to claim 1,wherein the gasket comprising at least one resinous material comprisesat least one material selected from one group consisting of butylrubber, ethylene-propylene rubber, chloroprene rubber and thermoplasticelastomer.
 9. The aerosol preparation according to claim 1, wherein thegasket comprising at least one resinous material comprises thethermoplastic elastomer, which is at least one rubber selected from arubber group consisting of butyl rubber, ethylene-propylene rubber andchloroprene rubber, mixed with at least one plastic selected from aplastic group consisting of polyethylene, polybutylene terephthalate,polyacetal, polyamide, polytetrafluoroethylene and polypropylene. 10.The aerosol preparation according to claim 9, wherein the at least onerubber and at the least one plastic of the thermoplastic elastomer is amixture of butyl rubber and polyethylene.
 11. The aerosol preparationaccording to claim 1, wherein the selected at least one resinousmaterial made into the gasket has a property such that, just after theresinous material having 39 mm² surface area has been soaked in the 10ml aerosol composition having the 0.025 wt % macrolide compound for amonth under a condition of 75% relative humidity and 40° C., the amountof the remaining macrolide compound in the aerosol composition is notless than 80% of the amount of the initial macrolide compound before thesoaking.
 12. The aerosol preparation according to claim 1, wherein thegasket comprises a neck gasket portion for ensuring airtightness of theenclosure, wherein the neck gasket portion comprises at least oneresinous material selected from the group consisting of butyl rubber,ethylene-propylene rubber, chloroprene rubber, polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene, polypropylene and thermoplastic elastomer. 13.The aerosol preparation according to claim 12, wherein the neck gasketportion comprising at least one resinous material comprises the butylrubber or the thermoplastic elastomer.
 14. The aerosol preparationaccording to claim 13, wherein the at least one resinous material is thethermoplastic elastomer and the thermoplastic elastomer is at least onerubber selected from a rubber group consisting of butyl rubber,ethylene-propylene rubber and chloroprene rubber, mixed with at leastone plastic selected from a plastic group consisting of polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene.
 15. The aerosol preparationaccording to claim 14, wherein the at least one rubber at the at leastone plastic of the thermoplastic elastomer made into the neck gasketportion is a mixture of butyl rubber and polyethylene.
 16. The aerosolpreparation according to claim 12, wherein the selected at least oneresinous material made into the neck gasket portion has a property suchthat, just after the resinous material having 39 mm² surface area hasbeen soaked in the 10 ml aerosol composition having the 0.025 wt %macrolide compound for a month under a condition of 75% relativehumidity and 40° C.,the amount of the remaining macrolide compound inthe aerosol composition is not less than 80% of the amount of theinitial macrolide compound before the soaking.
 17. The aerosolpreparation according to claim 1, wherein the valve part of theenclosure comprises: a metering chamber into which a fixed volume of theaerosol composition is taken out from the inside of the enclosure; and aslide member, wherein the slide member slides toward the inside of theenclosure so as to bring the metering chamber into communication with aninside of the enclosure, and wherein the slide member slides outwardfrom the enclosure so as to bring the metering chamber intocommunication with an outside of the enclosure and to spray out thefixed volume of the aerosol composition from the metering chamber, thegasket of the valve part including: a neck gasket portion for ensuringairtightness of the enclosure; a first gasket portion contacting theslide member so as to airtightly isolate the inside of the enclosurefrom the metering chamber; and a second gasket portion contacting theslide member so as to airtightly isolate the metering chamber from theoutside of the enclosure, wherein each of the neck gasket portion, thefirst gasket portion and the second gasket portion comprises at leastone resinous material selected from butyl rubber, ethylene-propylenerubber, chloroprene rubber, polyethylene, polybutylene terephthalate,polyacetal, polyamide, polytetrafluoroethylene, polypropylene andthermoplastic elastomer.
 18. The aerosol preparation according to claim17, wherein the neck gasket portion comprising at least one resinousmaterial comprises a thermoplastic elastomer which is at least onerubber selected from a rubber group consisting of butyl rubber,ethylene-propylene rubber and chloroprene rubber, mixed with at leastone plastic selected from a plastic group consisting of polyethylene,polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene, and wherein each of the firstand second gasket portions comprising at least one resinous materialcomprises butyl rubber, ethylene-propylene rubber or chloroprene rubber.19. The aerosol preparation according to claim 18, wherein the neckgasket portion comprising the thermoplastic elastomer comprises amixture of butyl rubber and polyethylene, and wherein each of the firstand second gasket portions comprising at least one resinous materialcomprises chloroprene rubber.
 20. The aerosol preparation according toclaim 17, wherein the selected at least one resinous material made intoeach of the neck gasket portion, the first gasket portion and the secondgasket portion has a property such that, just after the resinousmaterial having 39 mm² surface area has been soaked in the 10 ml aerosolcomposition having the 0.025 wt % macrolide compound for a month under acondition of 75% relative humidity and 40° C., the amount of theremaining macrolide compound in the aerosol composition is not less than80% of the amount of the initial macrolide compound before the soaking.21. The aerosol preparation according to claim 1, wherein the valve partcomprises a metering chamber member, a slide member and a housing,wherein at least one of the metering chamber member, the slide memberand the housing comprises at least one resinous material selected from aplastic group consisting of polyethylene, polybutylene terephthalate,polyacetal, polyamide, polytetrafluoroethylene and polypropylene. 22.The aerosol preparation according to claim 21, wherein the at least oneof the metering chamber member, the slide member and the housingcomprising at least one resinous material comprises polybutyleneterephthalate.
 23. The aerosol preparation according to claim 21,wherein the at least one of the metering chamber, the slide member andthe housing is made of resinous material having a property such that,just after the resinous material having 39 mm² surface area has beensoaked in the 10 ml aerosol composition having the 0.025 wt % macrolidecompound for a month under a condition of 75% relative humidity and 40°C., the amount of the remaining macrolide compound in the aerosolcomposition is not less than 80% of the amount of the initial macrolidecompound before the soaking.
 24. The aerosol preparation according toclaim 1, wherein the valve part comprises a protection ring comprisingat least one resinous material selected from a plastic group consistingof polyethylene, polybutylene terephthalate, polyacetal, polyamide,polytetrafluoroethylene and polypropylene.
 25. The aerosol preparationaccording to claim 24, wherein the protection ring comprising at leastone resinous material comprises polyethylene or polyamide.
 26. Theaerosol preparation according to claim 24, wherein the protection ringis made of resinous material having a property such that, just after theresinous material having 39 mm² surface area has been soaked in the 10ml aerosol composition having the 0.025 wt % macrolide compound for amonth under a condition of 75% relative humidity and 40° C., the amountof the remaining macrolide compound in the aerosol composition is notless than 80% of the amount of the initial macrolide compound before thesoaking.